Aminoglycoside antibiotics have long been used as bactericidal drugs.1 Unlike many antibiotics that are active only against gram positive bacteria, aminoglycosides have broad spectrum activity against both gram positive and negative bacteria. However, their clinical usage has often been limited only to serious infections due to the prevalence of aminoglycoside resistant bacteria1c,2 and the high cytotoxicity of aminoglycosides.3 In an effort to revive the effectiveness of aminoglycoside antibiotics against resistant bacteria, we have been working on modification and synthesis of novel aminoglycosides.
Over expression of aminoglycoside modifying enzymes from resistant bacteria is the most commonly encountered mode of resistance.2 Various aminoglycoside modifying enzymes have been identified that catalyze a wide range of modifications including acetylation, phosphorylation, and adenylation.
Aminoglycosides with deoxygenation at 3′-OH have been demonstrated to be effective against APH(3′) as reported by Umezawa1b,6 and others.7 The concept has led to the syntheses and discovery of tobramycin,8 arbekacin,9 and other similar aminoglycosides.1b Despite the fruitful results from these studies, there are several shortcomings. First, most of the research uses carbamate-type protecting groups for the protection of amino groups on the aminoglycoside, resulting in the formation of polycarbamate compounds with low solubility in organic media. The poor solubility of these compounds poses difficulties in their purification and characterization. Second, most of the syntheses begin with the kanamycin scaffold. There are very few examples of deoxygenation on neomycin class antibiotics.7d Third, the reported syntheses of both classes of antibiotics usually derive from kanamycin or neomycin, which limits the options for introducing novel structural motifs at other desirable places of aminoglycosides. Therefore, we have invented novel pyranmycin compounds with activity against resistant strains equipped with aminoglycoside modifying enzymes.